SNPwatch: Why You Gave Your Parents a Hard Time Growing Up

SNPwatch gives you the latest news about research linking various traits and conditions to individual genetic variations. These studies are exciting because they offer a glimpse into how genetics may affect our bodies and health; but in most cases, more work is needed before this research can provide information of value to individuals. For that reason, it is important to remember that the studies we describe in SNPwatch are for informational and educational purposes only. SNPwatch is not intended to be a substitute for professional medical advice; you should always seek the advice of your physician or other appropriate healthcare professional with any questions you may have regarding diagnosis, cure, treatment or prevention of any disease or other medical condition.

There are two simple ways to train animals to perform a new behavior: the carrot and the stick. The carrot rewards desired, “correct” behaviors, while the stick punishes “errors.” Over time, this scheme results in preference for positively reinforced behaviors, and avoidance of negatively reinforced ones. In the December 7 issue of Science, German scientists reported that the SNP rs1800497 is associated with how well subjects learn to avoid errors in a simple reward/punishment scheme. (What the paper calls the “A1-allele” of the “DRD2-TAQ-IA polymorphism” is actually what we store as the A version of the rs1800497 SNP, according to OMIM and and MutDB.)

Though we do not yet consider this finding solid enough to include in the Gene Journal (now called Health and Traits), 23andMe users can still examine their genotype at the rs1800497 using the Genome Explorer (now called Browse Raw Data). In the study, people with the GG genotype appeared to avoid choices for which they had received negative feedback, while those with the AG or AA genotypes did not seem to avoid those choices.

(There are currently no genetic associations for whether people prefer to be rewarded with actual carrots, although someone is clearly thinking about this question.)

Caveats

1) Study size. The authors only tested 12 subjects with the GG or AG genotype and 14 subjects with the AA genotype. This makes it more likely that the result could be a fluke (though the authors also present functional data to support their conclusions). At the very least, the training/testing portion of the study should be repeated in a much larger group. The same goes for other DRD2 association studies. 2) Real-world relevance. The test was highly abstract and the reinforcement simplistic and binary—this type of learning may not be relevant to real-world situations. 3) Multiple hypothesis testing. Other researchers have looked at whether this SNP is associated with behavioral traits from alcohol dependence to creativity, usually in undersized studies. If you run enough tests, something will eventually look like a positive hit just by chance.

(After the jump: detailed methods and smiley/scary faces.)

You Have Chosen…Poorly

How do you find out how well people learn? Give them a test where they have no idea what the correct answers are—and then reward or punish their choices!

During the training phase of this experiment, subjects took a series of trials. In each trial, they were presented with a pair of abstract symbols and asked to choose one. The subjects received immediate feedback about their choices: either a smiling face as a positive reinforcement (reward), or a frowning face as negative reinforcement (punishment).

The trials were repeated many times, using three different training pairs comprising six symbols—AB, CD, and EF. Of the possible choices, the most-rewarded choice was “A”, which received a happy face 80% of the time and a frowning face 20% of the time. The least-rewarded choice (and thus most punished) was “B”, which received a happy face only 20% of the time, and a frowning face 80% of the time. The reward schedule and the actual symbols used are in the figure to the right.

In the second phase, subjects were again asked to choose between two symbols. Although the same six symbols were used, in this phase the pairs did not include the three from the training set (i.e. BE and FD were shown, but not AB). The researchers measured preference for reward by recording the number of times the subjects chose “A” when it was offered. They measured avoidance of punishment by recording the number of times the subjects chose the non-“B” symbol when “B” was offered.

Those with the GG genotype at this SNP—avoiders—chose the non-“B” symbol 70% of the time. But those with the AA or AG genotypes—non-avoiders—chose the non-“B” symbol only 50% of the time, which is no different from choosing at random. The difference between avoiders and non-avoiders was of moderate statistical significance.Interestingly, there was no statistically significant difference between the two groups on preference for “A”—only for avoiding “B”.

Mechanism

The SNP occurs inside a gene called ANKK1, but scientists believe that the SNP acts on a neighboring gene, DRD2. The DRD2 gene encodes a receptor in the brain that responds to the neurotransmitter dopamine. At least two previous studies have shown that people with the AG and AA genotypes have lower levels of the dopamine D2 receptor in their brains. It’s possible that variation at the SNP affects how DRD2 is turned on and off, or that it is tightly linked to another SNP that does.

Klein et al. (2007) also used fMRI images of the brain to show that avoiders and non-avoiders had different activity levels in a zone of the brain thought to be involved in learning from errors. They suggest that “reduced dopamine D2 receptor density is associated with reduced capacity to learn negative characteristics of a stimulus from negative feedback.” In other words, if it’s true that people with the AG or AA genotypes make less of the dopamine D2 receptor, this might explain the reduction in activity they observed.

The authors also cite studies showing that lower dopamine D2 receptor density is linked to addiction, obesity, and novelty-seeking behaviors such as compulsive gambling, which suggests that non-avoiders in this study might also be prone to these behaviors. Interestingly, another study suggests that people with the same rs1800497 genotype as the non-avoiders (AA or AG) have higher verbal creativity.

Thanks for the tip. You’re absolutely right—the SNP lies in the neighboring ANKK1 gene. I mentioned this after the jump. There are several lines of evidence suggesting that the SNP influences expression levels of DRD2, meaning that the SNP might lie in a regulatory region for the DRD2 gene. An overlap between the regulatory region for one gene and the actual sequence of another gene is not uncommon.

The authors refer to the SNP as the “DRD2-TAQ-IA polymorphism.” Most likely this is because the polymorphism was discovered before the ANKK1 gene was. A decent history of the polymorphism is in OMIM.

Andro

http://genome.ciona.cnrs-gif.fr maximilianh

Hi Andro Hsu,
can you give a reference, for your claim “an overlap between the regulatory region for one gene and the actual sequence of another gene is not uncommon”. I’d say that this is very uncommon. I’d be interested in examples for this if you know some. If anything, than this is really rather the exception than a common case…
Max

http://genome.ciona.cnrs-gif.fr maximilianh

Hi Andro, just saw that I need to clarify this: I know quite a few examples where promoters/enhancers lie within a non-coding exon1. But in this case you speak about an overlap between a neighoring _coding_ sequence and the gene. I haven’t heard of regulatory sequences within coding sequences yet…
cheers,
max

http://www.23andme.com Andro Hsu

Hi Max,

You’re right; when I wrote “actual sequence” that seemed to imply that the regulatory region for a gene might lie in coding sequences of neighboring genes. If we go with the post-ENCODE definition of a gene (Gerstein et al. 2007), then my statement is definitely inaccurate. I don’t know of any human examples of promoters/enhancers lying in the open reading frame of an adjacent gene (though there might be in viruses, but that’s a different story).

A prominent example of a regulatory enhancer overlapping the (intronic) sequence of another gene is the SNP rs4988235, 13910 bases upstream of the LCT gene, which encodes lactase. The SNP affects LCT expression levels and is highly associated with lactase persistence/lactose intolerance. Lewinsky et al. (2005) have shown that the transcription factor Oct-1 binds directly to the SNP. Yet it’s located in the intron of a different gene, MCM6.

Andro

Betty

“which suggests that avoiders in this study might also be prone to these behaviors”

Is this backwards? Wouldn’t it suggest that the NON-avoiders, AA and AG, would be more prone to these behaviors?

http://23andme.com Shwu

Hi Betty,

Based on the previous paragraphs, you seem to be correct — we’ve updated the post accordingly!

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